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PMID: 11171976 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Expression of sterol regulatory element-binding protein 1c (SREBP-1c) mRNA in rat hepatoma cells requires endogenous LXR ligands.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 4 ·2001-02-13 ·Pages 1477-82

DeBose-Boyd RA, Ou J, Goldstein JL, Brown MS

Abstract

The current paper describes a line of cultured rat hepatoma cells (McA-RH7777 cells) that mimics the behavior of rat liver by producing an excess of mRNA for sterol regulatory element-binding protein 1c (SREBP-1c) as opposed to SREBP-1a. These two transcripts are derived from a single gene by use of alternative promoters that are separated by many kilobases in the genome. The high level of SREBP-1c mRNA is abolished when cholesterol synthesis is blocked by compactin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase that inhibits cholesterol synthesis. Levels of SREBP-1c mRNA are restored by mevalonate, the product of the HMG CoA reductase reaction, and by ligands for the nuclear hormone receptor LXR, including 22(R)-hydroxycholesterol and T0901317. These data suggest that transcription of the SREBP-1c gene in hepatocytes requires tonic activation of LXR by an oxysterol intermediate in the cholesterol biosynthetic pathway. Reduction of this intermediate lowers SREBP-1c levels, and this in turn is predicted to lower the rates of fatty acid biosynthesis in liver.

MeSH Terms
Animals CCAAT-Enhancer-Binding Proteins/genetics,metabolism Carcinoma, Hepatocellular Cholesterol/metabolism,pharmacology DNA-Binding Proteins/genetics,metabolism Gene Expression Humans Hydroxycholesterols/metabolism,pharmacology Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology Ligands Liver X Receptors Lovastatin/analogs & derivatives,pharmacology Orphan Nuclear Receptors RNA, Messenger Receptors, Cytoplasmic and Nuclear/metabolism Sterol Regulatory Element Binding Protein 1 Sterol Regulatory Element Binding Protein 2 Transcription Factors/genetics Tumor Cells, Cultured
Chemicals
CCAAT-Enhancer-Binding Proteins DNA-Binding Proteins Hydroxycholesterols Hydroxymethylglutaryl-CoA Reductase Inhibitors Ligands Liver X Receptors Orphan Nuclear Receptors RNA, Messenger Receptors, Cytoplasmic and Nuclear SREBF1 protein, human SREBF2 protein, human Sterol Regulatory Element Binding Protein 1 Sterol Regulatory Element Binding Protein 2 Transcription Factors 22-hydroxycholesterol mevastatin 25-hydroxycholesterol Cholesterol Lovastatin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
DeBose-Boyd R A
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.
Ou J
Goldstein J L
Brown M S
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.98.4.1477
Published
2001-02-13
Pages
1477-82
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC29282
Subset
IM
Grants
NHLBI NIH HHS · P01 HL020948 · United States
External Links
PubMed source DOI: 10.1073/pnas.98.4.1477 PMC Full Text View journal details
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